1-isocyanato-2-methylbenzene -Drug Synthesis Database

【结构式】

【分子编号】27106

【品名】1-isocyanato-2-methylbenzene

【CA登记号】614-68-6

【分子式】C₈H₇NO

【分子量】133.14972

【元素组成】C 72.17% H 5.3% N 10.52% O 12.02%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XI)

Condensation of o-tolyl isocyanate (XI) with 4-aminophenylacetic acid (XII) produced urea (XIII). This was coupled to tetrapeptide (X) using EDC and HOBt to give the corresponding amide (XIV). Finally, the benzyl ester groups of (XIV) were deprotected by hydrogenolysis over Pd/C.

参考文献中间体

合成目标

【1】 Ateeq, H.S.; Lin, K.-C.; Hsiung, S.H.; et al.; Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem 1999, 42, 5, 920.
【2】 Lin, K.-C.; Adams, S.P.; Castro, A.C.; Zimmerman, C.N.; Cuervo, J.H.; Lee, W.-C.; Hammond, C.E.; Carter, M.B.; Almquist, R.G.; Ensinger, C.L. (Biogen, Inc.); Cell adhesion inhibitor. EP 0842196; JP 1999511124; WO 9703094 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	27105	benzyl (2S)-1-((2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-4-(benzyloxy)-4-oxobutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate		C₃₄H₄₆N₄O₇	详情	详情
(XI)	27106	1-isocyanato-2-methylbenzene	614-68-6	C₈H₇NO	详情	详情
(XII)	21229	2-(4-Aminophenyl)acetic acid	5345-54-0	C₈H₉NO₂	详情	详情
(XIII)	27107	2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid		C₁₆H₁₆N₂O₃	详情	详情
(XIV)	27108	benzyl (2S)-1-((2S)-2-[[(2S)-4-(benzyloxy)-2-([(2S)-4-methyl-2-[(2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]pentanoyl]amino)-4-oxobutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate		C₅₀H₆₀N₆O₉	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Reaction of 2-nitroanisole (I) with methyl dichloroacetate (II) in the presence of potassium tert-butoxide at -5 C produced the arylacetic acid derivative (III). Hydrogenation of (III) over Pd/C produced both reduction of the nitro group and hydrogenolysis of the halogen atom to afford amine (IV), which was then condensed with o-tolyl isocyanate (V) giving urea (VI). Basic hydrolysis of the methyl ester of (VI) provided the corresponding acid (VII). This was coupled with glycine methyl ester (VIII) using EDC and HOBt to yield amide (IX). Then, ester (IX) hydrolysis with LiOH gave rise to carboxylic acid.

参考文献中间体

合成目标

【1】 Morley, A.D.; Harris, N.V.; Astles, P.C. (Rhone-Poulenc Rorer Ltd.); Substd. beta-alanines. WO 9933789 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	39714	methyl 2-nitrophenyl ether; 1-methoxy-2-nitrobenzene	91-23-6	C₇H₇NO₃	详情	详情
(II)	36413	methyl 2,2-dichloroacetate	116-54-1	C₃H₄Cl₂O₂	详情	详情
(III)	39715	methyl 2-chloro-2-(3-methoxy-4-nitrophenyl)acetate		C₁₀H₁₀ClNO₅	详情	详情
(IV)	39716	methyl 2-(4-amino-3-methoxyphenyl)acetate		C₁₀H₁₃NO₃	详情	详情
(V)	27106	1-isocyanato-2-methylbenzene	614-68-6	C₈H₇NO	详情	详情
(VI)	39717	methyl 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetate		C₁₈H₂₀N₂O₄	详情	详情
(VII)	39718	2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid		C₁₇H₁₈N₂O₄	详情	详情
(VIII)	17568	methyl 2-aminoacetate		C₃H₇NO₂	详情	详情
(IX)	39719	methyl 2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetate		C₂₀H₂₃N₃O₅	详情	详情
(X)	39720	2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetic acid		C₁₉H₂₁N₃O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

Coupling of p-aminophenylacetic acid (IX) with o-tolyl isocyanate (X) produces urea (XI). This is subsequently condensed with the intermediate tripeptide (VIII) in the presence of HATU to yield amide (XII). Hydrogenolysis of the N-benzyloxycarbonyl group of (XII) then gives amine (XIII). Finally, acylation of amine (XIII) with 3,5-dichlorobenzensulfonyl chloride (XIV), followed by alkaline hydrolysis of the methyl ester group furnishes the title compound.

参考文献中间体

合成目标

【1】 Lee, W.-C.; Scott, D.; Cornebise, M.; Petter, R. (Biogen Idec Inc.); Cell adhesion inhibitors. EP 1265606; JP 2003506491; US 6630503; WO 0112186 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	64990	phenylmethyl 2-[({3-{[4-methyl-2-(methylamino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate		C₂₅H₃₈N₄O₆	详情	详情
(IX)	21229	2-(4-Aminophenyl)acetic acid	5345-54-0	C₈H₉NO₂	详情	详情
(X)	27106	1-isocyanato-2-methylbenzene	614-68-6	C₈H₇NO	详情	详情
(XI)	27107	2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid		C₁₆H₁₆N₂O₃	详情	详情
(XII)	64991	phenylmethyl 2-[({3-{[4-methyl-2-(methyl{2-[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate		C₄₁H₅₂N₆O₈	详情	详情
(XIII)	64992	methyl 4-{[4-methyl-2-(methyl{2-[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)pentanoyl]amino}-2-[(2-pyrrolidinylcarbonyl)amino]butanoate		C₃₃H₄₆N₆O₆	详情	详情
(XIV)	59023	3,5-dichlorobenzenesulfonyl chloride		C₆H₃Cl₃O₂S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

The condensation of 5-chloro-2-nitroanisole (V) with diethyl malonate (VI) by means of NaH in hot DMF gives 2-(3-methoxy-4-nitrophenyl)malonic acid diethyl ester (VII), which is reduced with H2 over Pd/C in ethyl acetate, yielding the corresponding amino derivative (VIII). The condensation of (VIII) with 2-methylphenyl isocyanate (IX) by means of TEA in dichloromethane affords the expected urea (X), which is submitted to a decarboxylative hydrolysis with NaOH in refluxing tert-butanol to provide the phenylacetic acid (XI). The condensation of acetic acid (XI) with the amino group of the isoxazole intermediate (IV) by means of HOBt, DIEA and EDC in DMF gives the amide (XII), which is treated with NaOH in tert-butanol to afford the target propionic acid.

参考文献中间体

合成目标

【1】 Duplantier, A.J.; et al.; Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha4beta1 integrin antagonists. Bioorg Med Chem Lett 2001, 11, 19, 2593.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	51635	methyl 3-[3-[(1S)-1-amino-3-methylbutyl]-5-isoxazolyl]propanoate		C₁₂H₂₀N₂O₃	详情	详情
(V)	51636	4-Chloro-2-methoxy-1-nitrobenzene; 4-Chloro-2-methoxynitrobenzene; 5-Chloro-2-nitroanisole	6627-53-8	C₇H₆ClNO₃	详情	详情
(VI)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(VII)	51637	diethyl 2-(3-methoxy-4-nitrophenyl)malonate		C₁₄H₁₇NO₇	详情	详情
(VIII)	51638	diethyl 2-(4-amino-3-methoxyphenyl)malonate		C₁₄H₁₉NO₅	详情	详情
(IX)	27106	1-isocyanato-2-methylbenzene	614-68-6	C₈H₇NO	详情	详情
(X)	51639	diethyl 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]malonate		C₂₂H₂₆N₂O₆	详情	详情
(XI)	39718	2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid		C₁₇H₁₈N₂O₄	详情	详情
(XII)	51640	methyl 3-(3-[(1S)-1-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]-3-methylbutyl]-5-isoxazolyl)propanoate		C₂₉H₃₆N₄O₆	详情	详情

Extended Information